Understanding partial epileptogenesis in cellular and molecular terms may provide clues as to how to intervene pharmacologically to prevent this disorder. A commonly studied animal model of epileptogenesis is kindling in which pathological activity in the form of focal seizures induces epilepsy. The neurotrophins represent a family of molecules implicated in linking fleeting changes in activity to long term changes in neuronal phenotype. Striking increases in transcription of two neurotrophins, BDNF and NGF, occur in hippocampal neurons in the kindling model, but whether either or both of these neurotrophins promote epileptogenesis is uncertain. We have also obtained immunohistochemical evidence of enhanced activation of trk receptors in the hippocampus in multiple models of epileptogenesis. The objective of this proposal is to test different aspects of our unifying hypothesis which predicts that glutamate receptor activation during seizures triggers the transcription, translation, and release of BDNF, resulting in enhanced activation of trkB. Activation of trkB in turn activates diverse signal transduction pathways which trigger morphological and/or functional plasticities which culminate in a hyperexcitable state. The specific aims are fivefold: a) to further characterize the role of neurotrophins in limbic epileptogenesis; b) to characterize the molecular nature of the phophotrk immunoreactivity; c) to determine which neurotrophin(s) mediate the increased phosphotrk immunoreactivity; d) to investigate the signal transduction pathways by which trkB activation promotes epileptogenesis; 3) to determine the cellular locale of the kindling-induced increase of phosphotrk immunoreactivity. These specific aims will be accomplished by pharmacological, biochemical, and immunohistochemical studies of rats and mice, including mice in which a single gene has been deleted or modified at a single residue. Accomplishing these specific aims may provide novel therapeutic approaches aimed at prevention of epilepsy.